Crystal polymorph of magnesium glycinate dihydrate and process for its preparation

ABSTRACT

Embodiments of the invention provide solid forms of magnesium glycinate dihydrate and compositions thereof, which are useful for treating hyperphosphatemia and which exhibit desirable characteristics for the same. The invention further provides processes for the production of solid forms of magnesium glycinate dihydrate.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 USC §119(e) of U.S.Provisional Application No. 61/731,885, filed Nov. 30, 2012, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides solid forms of a compound of magnesiumglycinate dihydrate, which may be characterized by increased phosphatebinding capacity. The invention also provides pharmaceuticallyacceptable compositions comprising solid forms of the present inventionand methods of using the compositions in the treatment of variousdisorders. The invention also provides methods of producing the novelsolid forms disclosed herein.

BACKGROUND OF THE INVENTION

Like other diseases for which there is no cure, chronic kidney diseasetakes an ever-increasing toll on patients who have it. As the diseaseprogresses, the kidney becomes less efficient at removing various ionsfrom the blood. Among these ions is phosphate, which can form insolubleparticles when combined with calcium. In end-stage renal disease, thefinal stage of chronic kidney disease, kidney function is so compromisedthat phosphate levels in the blood (serum) become markedly elevated.This condition, known as hyperphosphatemia, carries with it many gravehealth risks. For example, when serum phosphate and calcium levels areabove a certain threshold, hardened deposits may form throughout thebody, endangering circulation. It is therefore very important to controlserum phosphate levels in patients with end-stage renal disease.

Patients with end-stage renal disease may be advised to eat a diet lowin phosphate. However, phosphate is present at some level in almost allthe foods we eat. For this reason, phosphate binders were developed.Phosphate binders are compounds taken orally and which act in thegastrointestinal tract to bind phosphate and keep it from beingabsorbed. Phosphate binders are generally taken with each meal.Phosphate binders known in the art include, for example, various saltsof aluminum and calcium, as well as some chemically synthesizedcrosslinked polymers. There are clinical circumstances in which theadministration of aluminum or calcium salts is ill-advised. In animalmodels, certain crosslinked polymers carry with them elevated risks ofcarcinogenesis. Therefore, there is a need for safer and more effectivephosphate binders.

SUMMARY OF THE INVENTION

It has now been found that the novel solid forms of the presentinvention generated by the processes disclosed herein, and compositionsthereof, are useful for the treatment of hyperphosphatemia and exhibitdesirable characteristics for the same. In general, these solid forms,and pharmaceutically acceptable compositions thereof, are useful fortreating or lessening the severity of a variety of diseases or disordersas described in detail herein.

Embodiments of the invention comprise a crystalline dihydrate form ofmagnesium glycinate (formula I)

In some embodiments, the form is characterized by an X-ray powderdiffraction pattern having one or more peaks selected from those atabout 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1. Insome embodiments the form is characterized by an X-ray powderdiffraction pattern having two or more peaks selected from those atabout 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1. Insome embodiments, the form is characterized by an X-ray powderdiffraction pattern having three or more peaks selected from those atabout 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1. Insome embodiments, the form has substantially all of the peaks in itsX-ray powder diffraction pattern selected from those at about 14.6,16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1. In someembodiments, the form has substantially all of the peaks in its X-raypowder diffraction pattern selected from those at about:

No. 2-Theta ° Δ 2θ (±)° d, Å 1 14.6 0.1 6.06 2 16.0 0.1 5.54 3 16.9 0.15.25 4 17.6 0.1 5.04 5 19.3 0.1 4.59 6 22.9 0.1 3.88 7 24.4 0.1 3.65 825.8 0.1 3.46 9 30.9 0.1 2.89 10 47.1 0.1 1.93

In some embodiments, the crystalline magnesium glycinate dihydrate has aspace group P21/n. In some embodiments, the crystalline magnesiumglycinate dihydrate has unit cell dimensions of about a=7.5 Å, b=9.0 Å,and c=13.0 Å. In some embodiments, the crystalline magnesium glycinatedihydrate has unit cell dimensions of about a=7.548 Å, b=9.053 Å, andc=12.970 Å. In some embodiments, the crystalline magnesium glycinatedihydrate has unit cell dimensions of about a=7.575 Å, b=9.153 Å, andc=13.052 Å.

In some embodiments, a crystalline magnesium glycinate dihydrate form ischaracterized by one or more of the following structural parameters:

Empirical formula C₄H₁₂MgN₂O₆ Formula weight  208.47 Temperature 147(2)K Wavelength 1.54178 Å Crystal system Monoclinic Space group P 21/n Unitcell dimensions a = 7.5481(3) Å α = 90° b = 9.0525(3) Å β = 98.612(3)° c= 12.9702(5) Å γ = 90° Volume 876.25(6) Å³ Z   4 Density (calculated)1.580 Mg/m³ Absorption coefficient 1.893 mm⁻¹ F(000)  440 Crystal size0.10 × 0.01 × 0.01 mm³ Theta range for data collection 5.98 to 66.64°Index ranges −8 <= h <= 7, −10 <= k <= 10, −10 <= l <= 15 Reflectionscollected 5746 Independent reflections 1501 [R(int) = 0.0279]Completeness to theta = 66.64° 97.2% Absorption correctionSemi-empirical from equivalents Max. and min. transmission 0.7528 and0.6842 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 1501/0/150 Goodness-of-fit on F²   1.056Final R indices [I > 2sigma(I)] R1 = 0.0269, wR2 = 0.0696 R indices (alldata) R1 = 0.0303, wR2 = 0.0718 Largest diff. peak and hole 0.215 and−0.224 e · Å⁻³

In another aspect of the invention, there is provided a pharmaceuticalcomposition comprising crystalline form(s) of magnesium glycinatedihydrate as described herein. Some embodiments of the pharmaceuticalcomposition comprise an enteric coating. In some embodiments, theenteric coating comprises acetyltributyl citrate, carbomers, celluloseacetate phthalate, cellulose acetate succinate, ethyl cellulose, guargum, hypromellose acetate succinate, hypromellose phthalate,polymethacrylates, polyvinyl acetate phthalate, shellac, tributylcitrate, triethyl citrate, white wax and/or zein. In certainembodiments, the enteric coating that is stable at pH less than 3 butdissolves at a pH above 5.5. In some embodiments, the pharmaceuticalcomposition further comprises one or more additional therapeutic agentsor nutrients. Nutrients may be selected from vitamins, minerals, fattyacids, and/or amino acids.

Another aspect of the invention provides methods of treatinghyperphosphatemia in a subject comprising administering to the subject aform of the magnesium glycinate dihydrate disclosed herein. In someembodiments, the form is a component of the pharmaceutical compositionsdisclosed herein.

In another aspect of the invention, there is provided processes ofmanufacturing magnesium glycinate dihydrate comprising dissolvingmagnesium methoxide and glycine in methanol. Some embodiments furthercomprise heating the solution. Some embodiments further comprise addinga volume of water to the mixture. Some embodiments further compriseheating the solution a second time. Some embodiments further compriseprecipitating magnesium glycinate dihydrate from the mixture. Inparticular embodiments, the mixture of magnesium methoxide and glycineis heated at approximately 50-55° C. for at least 30 minutes. In certainembodiments, precipitating magnesium glycinate dihydrate comprisescooling to less than 25° C. for at least 30 minutes.

In another aspect of the invention, there is provided a crystallinepolymorph of magnesium glycinate dihydrate made by the processesdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the x-ray powder diffraction (XRPD) pattern for twosamples of a compound and of the invention and compares those patternsto a spectra calculated from a single crystal-derived x-ray structure ofthe compound.

FIG. 2 depicts the crystal lattice structure of magnesium glycinatedihydrate.

FIG. 3 depicts the solution structure of a single dihydrated complex ofmagnesium glycinate. It shows two water molecules coordinated as thedihydrate.

FIG. 4 is a flow diagram of a manufacturing process that may be used toproduce solid forms of the invention.

DETAILED DESCRIPTION OF THE INVENTION

General Description of Certain Aspects of the Invention:

U.S. application Ser. No. 12/422,012 (“the '012 application”), now U.S.Pat. No. 8,247,000, filed Apr. 10, 2009, the entirety of which is herebyincorporated herein by reference, describes compositions of magnesiumglycinate salt characterized by an ability to bind at least 50 mgphosphate per gram in an in vitro phosphate binding assay, which aresuitable for treatment of hyperphosphatemia. Such compounds, which maybe represented by the structure below, include formulations for oraladministrations and enteric coatings:

Related U.S. Pat. No. 8,236,358, also incorporated by reference herein,describes methods of treating hyperphosphatemia with magnesium glycinatecompositions.

Different preparations and forms of magnesium glycinate may becharacterized by different phosphate binding capacities. In other words,particular solid forms of magnesium glycinate can be characterized bytheir phosphate-binding capacity as determined by variousphosphate-binding assays known in the art. In some embodiments, solidforms of magnesium glycinate dihydrate can be characterized by theirphosphate binding capacity under conditions that simulate smallintestinal fluid (SIF), where said forms exhibit therapeutic action inmammalian subjects. Exemplary phosphate-binding assays in solutionssimulating SIF are described in the '012 application. Additionalphosphate-binding assays are described in Rosenbaum et al. Nephrol.Dial. Transplant. 12:961-964 (1997); and Lowry & Lopez J. Biol. Chem.162:421-428 (1946), the teachings of which are incorporated by referenceherein.

It would be desirable to provide a solid form of magnesium glycinatethat, as compared to known forms, imparts characteristics such asimproved aqueous solubility, stability, ease of formulation and ismorphologically pure. Accordingly, the present invention provides novelsolid forms of magnesium glycinate. Furthermore, embodiments of theinvention comprise novel methods for production of said solid forms.Additional embodiments of the invention provide methods of treatinghyperphosphatemia using the novel solid forms of magnesium glycinate.

Accordingly, embodiments of the invention provide solid crystallineforms of magnesium glycinate. Exemplary solid forms are described inmore detail below, including particular embodiments of magnesiumglycinate dihydrate.

In some embodiments, the present invention provides magnesium glycinateforms substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude starting materials, residual solvents, or any other impuritiesthat may result from the preparation of, and/or isolation of, magnesiumglycinate. In preferred embodiments, the magnesium glycinate forms aresubstantially free of magnesium hydroxide. In certain embodiments, atleast about 95% by weight of magnesium glycinate is present. In stillother embodiments of the invention, at least about 99% by weight ofmagnesium glycinate is present.

According to one embodiment, a novel magnesium glycinate form is presentin an amount of at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, or99.8 weight percent where the percentages are based on the total weightof the composition. According to another embodiment, a novel magnesiumglycinate form contains no more than about 3.0 area percent HPLC oftotal organic impurities and, in certain embodiments, no more than about1.5 area percent HPLC total organic impurities relative to the totalarea of the HPLC chromatogram. In other embodiments, a novel magnesiumglycinate form contains no more than about 1.0 area percent HPLC of anysingle impurity; no more than about 0.6 area percent HPLC of any singleimpurity, and, in certain embodiments, no more than about 0.5 areapercent HPLC of any single impurity, relative to the total area of theHPLC chromatogram.

The novel magnesium glycinate forms also include all tautomeric forms.Additionally, structures depicted here are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structureexcept for the replacement of hydrogen by deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention.

Embodiments of the present invention include pharmaceutical compositionscomprising magnesium glycinate dihydrate in substantially polymorph formdescribed by one or more x-ray powder diffraction peaks described belowand exemplified in FIG. 1. The pharmaceutical compositions may beadministered to a subject in need thereof in any dosage form; forexample, those described in the '012 application.

According to another aspect of the invention, a process for thepreparation of magnesium glycinate dihydrate is provided. In certainembodiments, the process results in magnesium glycinate dihydrate insubstantially polymorph form described by one or more x-ray powderdiffraction peaks described below and exemplified in FIG. 1.

Solid Forms of Magnesium Glycinate:

It has been found that magnesium glycinate can exist in a variety ofsolid forms. Such forms may be amorphous. Moreover, magnesium glycinatecan exist in a variety of crystalline forms, called polymorphs. Thesolid forms can be solvates, hydrates and unsolvated forms of magnesium.All such forms are contemplated by the present invention. In certainembodiments, the present invention provides magnesium glycinate as amixture of one or more solid forms of magnesium glycinate. In aparticular embodiment, the present invention provides magnesiumglycinate as a dihydrated polymorph.

As used herein, the term “polymorph” refers to the different crystalstructures (of solvated or unsolvated forms) in which a compound cancrystallize.

As used herein, the term “solvate” refers to a solid form with either astoichiometric or non-stoichiometric amount of solvent (e.g., a channelsolvate). For polymorphs, the solvent is incorporated into the crystalstructure. Similarly, the term “hydrate” refers to a solid form witheither a stoichiometric or non-stoichiometric amount of water. Forpolymorphs, the water is incorporated into the crystal structure.

As used herein, the term “about”, when used in reference to a degree2-theta value refers to the stated value ±0.3 degree 2-theta. In certainembodiments, “about” refers to ±0.2 degree 2-theta or ±0.1 degree2-theta.

In certain embodiments, magnesium glycinate dihydrate is a crystallinesolid. In some embodiments, magnesium glycinate dihydrate is acrystalline solid substantially free of amorphous magnesium glycinate.As used herein, the term “substantially free of amorphous magnesiumglycinate” means that the compound contains no significant amount ofamorphous magnesium glycinate. In certain embodiments, at least about95% by weight of crystalline magnesium glycinate dihydrate is present.In still other embodiments of the invention, at least about 97%, 98% or99% by weight of crystalline magnesium glycinate dihydrate is present.

In certain embodiments, the present invention provides a crystal form ofmagnesium glycinate dihydrate. According to one embodiment, the form ischaracterized in that it has one or more peaks in its powder X-raydiffraction pattern selected from those at about 14.6, 16.0, 16.9, 17.6,19.3, 22.9, 24.4, 25.8, 30.9 or 47.1 degrees 2-theta. In someembodiments, the form is characterized in that it has two or more peaksin its powder X-ray diffraction pattern selected from those at about14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1 degrees2-theta. In certain embodiments, the form is characterized in that ithas three or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9or 47.1 degrees 2-theta. In particular embodiments, the form ischaracterized in having substantially all of the peaks in its X-raypowder diffraction pattern selected from those at about 14.6, 16.0,16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1 degrees 2-theta. In anexemplary embodiment, the form is characterized in having substantiallyall of the peaks in its X-ray powder diffraction pattern selected fromthose at about:

TABLE 1 No. 2-Theta ° Δ 2θ (±)° d, Å 1 14.6 0.1 6.06 2 16.0 0.1 5.54 316.9 0.1 5.25 4 17.6 0.1 5.04 5 19.3 0.1 4.59 6 22.9 0.1 3.88 7 24.4 0.13.65 8 25.8 0.1 3.46 9 30.9 0.1 2.89 10 47.1 0.1 1.93

According to one aspect, the form has a powder X-ray diffraction patternsubstantially similar or essentially identical to that depicted inFIG. 1. According to another aspect, the form has a crystal latticestructure substantially similar to that depicted in FIG. 2. Accordinglyto yet another aspect, the form is a single dihydrated complexsubstantially similar to that depicted in FIG. 3. The form can becharacterized by substantial similarity to two or more of these figuressimultaneously.

According to another embodiment of the invention, there is provided acrystalline polymorph of magnesium glycinate dihydrate that ischaracterized by one or more of the crystal structure parameters as setforth in Table 2 below:

TABLE 2 Empirical formula C₄H₁₂MgN₂O₆ Formula weight  208.47 Temperature147(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P21/n Unit cell dimensions a = 7.5481(3) Å α = 90° b = 9.0525(3) Å β =98.612(3)° c = 12.9702(5) Å γ = 90° Volume 876.25(6) Å³ Z   4 Density(calculated) 1.580 Mg/m³ Absorption coefficient 1.893 mm⁻¹ F(000)  440Crystal size 0.10 × 0.01 × 0.01 mm³ Theta range for data collection 5.98to 66.64° Index ranges −8 <= h <= 7, −10 <= k <= 10, −10 <= l <= 15Reflections collected 5746 Independent reflections 1501 [R(int) =0.0279] Completeness to theta = 66.64° 97.2% Absorption correctionSemi-empirical from equivalents Max. and min. transmission 0.7528 and0.6842 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 1501/0/150 Goodness-of-fit on F²   1.056Final R indices [I > 2sigma(I)] R1 = 0.0269, wR2 = 0.0696 R indices (alldata) R1 = 0.0303, wR2 = 0.0718 Largest diff. peak and hole 0.215 and−0.224 e · Å⁻³

The unit cell dimensions are defined by three parameters: length of thesides of the cell; relative angles of the sides to each other and thevolume of the cell. The lengths of the sides of the unit cell aredefined by a, b and c. The relative angles of the cell sides are definedby α, β and γ.

Embodiments of the invention further include crystalline magnesiumglycinate dihydrate having atomic positions of all the atoms relative tothe origin of the unit cell as recited in Tables 3-6 and represented inFIG. 3. Tables 3 through 6 list the parameters of atomic coordinates andtheir isotropic displacement parameters, bond lengths and angles,anisotropic displacement parameters and hydrogen (proton) atomcoordinates of crystalline magnesium glycinate dihydrate as describedherein. These parameters define the absolute atomic arrangement in thecrystal structure of magnesium glycinate dihydrate depicted in FIGS. 2and 3.

TABLE 3 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for d12119. U(eq) is defined as one third of thetrace of the orthogonalized U^(ij) tensor. x y z U(eq) Mg(1) 4955(1)3183(1) 1604(1) 12(1) O(1) 6599(1) 1363(1) 1488(1) 16(1) O(2) 7777(2)−198(1)  443(1) 20(1) O(3) 3002(1) 4804(1) 1397(1) 16(1) O(4)  85(1)5319(1) 1178(1) 19(1) O(5) 5111(2) 3108(1) 3184(1) 20(1) O(6) 6936(2)4761(1) 1775(1) 16(1) N(1) 4885(2) 2953(2) −109(1) 17(1) N(2) 2478(2)1838(1) 1541(1) 16(1) C(1) 6247(2) 1896(2) −337(1) 17(1) C(2) 6920(2) 936(2)  601(1) 14(1) C(3)  910(2) 2796(2) 1257(1) 18(1) C(4) 1384(2)4431(2) 1281(1) 14(1)

TABLE 4 Bond lengths [Å] and angles [°] for Magnesium GlycinateDihydrate Polymorph Mg(1)—O(5) 2.0365(12)  Mg(1)—O(6) 2.0566(12) Mg(1)—O(3) 2.0685(11)  Mg(1)—O(1) 2.0817(11)  Mg(1)—N(2) 2.2224(14) Mg(1)—N(1) 2.2249(14)  O(1)—C(2) 1.2702(18)  O(2)—C(2) 1.2464(18) O(3)—C(4) 1.2548(18)  O(4)—C(4) 1.2591(18)  O(5)—H(1O) 0.85(3)O(5)—H(2O) 0.83(3) O(6)—H(3O) 0.83(2) O(6)—H(4O) 0.87(3) N(1)—C(1)1.466(2)  N(1)—H(1N) 0.86(2) N(1)—H(2N) 0.92(2) N(2)—C(3) 1.469(2) N(2)—H(3N) 0.86(2) N(2)—H(4N) 0.90(2) C(1)—C(2) 1.519(2)  C(1)—H(1A)0.9900 C(1)—H(1B) 0.9900 C(3)—C(4) 1.522(2)  C(3)—H(3A) 0.9900C(3)—H(3B) 0.9900 O(5)—Mg(1)—O(6) 89.02(5)  O(5)—Mg(1)—O(3) 94.99(5) O(6)—Mg(1)—O(3) 90.77(5)  O(5)—Mg(1)—O(1) 95.83(5)  O(6)—Mg(1)—O(1)97.23(5)  O(3)—Mg(1)—O(1) 166.63(5)  O(5)—Mg(1)—N(2) 86.58(5) O(6)—Mg(1)—N(2) 168.22(5)  O(3)—Mg(1)—N(2) 78.74(5)  O(1)—Mg(1)—N(2)94.09(5)  O(5)—Mg(1)—N(1) 172.49(5)  O(6)—Mg(1)—N(1) 94.64(5) O(3)—Mg(1)—N(1) 91.52(5)  O(1)—Mg(1)—N(1) 77.22(5)  N(2)—Mg(1)—N(1)91.05(5)  C(2)—O(1)—Mg(1) 120.19(9)  C(4)—O(3)—Mg(1) 119.13(9) Mg(1)—O(5)—H(1O) 116.3(14) Mg(1)—O(5)—H(2O) 122.5(17) H(1O)—O(5)—H(2O) 111(2) Mg(1)—O(6)—H(3O) 127.8(15) Mg(1)—O(6)—H(4O) 120.5(15)H(3O)—O(6)—H(4O)  105(2) C(1)—N(1)—Mg(1) 110.45(9)  C(1)—N(1)—H(1N)108.1(14) Mg(1)—N(1)—H(1N) 121.8(14) C(1)—N(1)—H(2N) 109.8(14)Mg(1)—N(1)—H(2N) 102.1(13) H(1N)—N(1)—H(2N)  104(2) C(3)—N(2)—Mg(1)109.09(9)  C(3)—N(2)—H(3N) 107.8(13) Mg(1)—N(2)—H(3N) 113.1(13)C(3)—N(2)—H(4N) 110.7(13) Mg(1)—N(2)—H(4N) 109.8(13) H(3N)—N(2)—H(4N)106.3(18) N(1)—C(1)—C(2) 111.88(12)  N(1)—C(1)—H(1A) 109.2C(2)—C(1)—H(1A) 109.2 N(1)—C(1)—H(1B) 109.2 C(2)—C(1)—H(1B) 109.2H(1A)—C(1)—H(1B) 107.9 O(2)—C(2)—O(1) 124.97(13)  O(2)—C(2)—C(1)117.32(13)  O(1)—C(2)—C(1) 117.69(13)  N(2)—C(3)—C(4) 113.06(12) N(2)—C(3)—H(3A) 109.0 C(4)—C(3)—H(3A) 109.0 N(2)—C(3)—H(3B) 109.0C(4)—C(3)—H(3B) 109.0 H(3A)—C(3)—H(3B) 107.8 O(3)—C(4)—O(4) 124.72(14) O(3)—C(4)—C(3) 119.04(13)  O(4)—C(4)—C(3) 116.24(13) 

TABLE 5 Anisotropic displacement parameters (Å² × 10³) for MagnesiumGlycinate Dihydrate Polymorph. The anisotropic displacement factorexponent takes the form: −2p²[h² a*²U¹¹+ . . . +2 h k a* b* U¹²] U¹¹ U²²U³³ U²³ U¹³ U¹² Mg(1) 13(1) 11(1) 13(1)  0(1) 1(1)  1(1) O(1) 18(1)15(1) 13(1)  0(1) 2(1)  4(1) O(2) 24(1) 18(1) 18(1) −2(1) 1(1)  9(1)O(3) 13(1) 13(1) 23(1)  0(1) 3(1) −1(1) O(4) 15(1) 17(1) 25(1) −2(1)5(1)  4(1) O(5) 29(1) 16(1) 15(1)  0(1) 1(1) −7(1) O(6) 14(1) 19(1)17(1) −3(1) 4(1) −2(1) N(1) 21(1) 15(1) 16(1)  3(1) 2(1)  4(1) N(2)18(1) 13(1) 16(1) −1(1) 2(1)  0(1) C(1) 19(1) 19(1) 14(1)  2(1) 4(1) 4(1) C(2) 12(1) 14(1) 16(1) −1(1) 1(1) −2(1) C(3) 14(1) 15(1) 26(1)−2(1) 3(1) −1(1) C(4) 16(1) 16(1) 10(1) −2(1) 4(1)  1(1)

TABLE 6 Hydrogen (proton) coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for Magnesium Glycinate Dihydrate Polymorph. x y zU(eq) H(1A) 7268 2442 −551 21 H(1B) 5731 1257 −926 21 H(3A) 44 2613 174522 H(3B) 319 2533 548 22 H(1O) 5010(30) 2250(30) 3452(17) 40(6) H(2O)5800(30) 3640(30) 3578(19) 48(7) H(3O) 7850(30) 4790(20) 1495(16) 35(6)H(4O) 7220(30) 5230(30) 2370(20) 44(6) H(1N) 4920(30) 3710(30) −509(17)37(6) H(2N) 3750(30) 2570(20) −317(17) 40(6) H(3N) 2410(30) 1140(20)1092(15) 28(5) H(4N) 2450(30) 1410(20) 2164(16) 32(5)General Methods of Providing Magnesium Glycinate Dihydrate:

Crystalline polymorphic magnesium glycinate (e.g., magnesium glycinatedihydrate of the polymorph form described herein) can be obtained by thefollowing processes. Those of skill in the art will appreciate that theprocesses described below may be modified or adapted to producedifferent polymorphic forms (e.g., by changing solvents, combinations ofsolvents or temperature), monohydrates or multihydrates (e.g., byadjusting water content in a given solvent). Various solid forms ofmagnesium glycinate can be prepared by dissolving the compound invarious suitable solvents and then causing the magnesium glycinate toreturn to the solid phase. Specific combinations of solvents andconditions under which magnesium glycinate returns to the solid phaseare discussed in greater detail below. In a particular embodiment,magnesium glycinate dihydrate is obtained by heating magnesium methoxideand glycine under conditions described below.

A suitable solvent may solubilize magnesium glycinate and or itsprecursors (e.g., magnesium methoxide or glycine), either partially orcompletely. Examples of suitable solvents useful in the presentinvention are a protic solvent, a polar aprotic solvent, or mixturesthereof. In certain embodiments, suitable solvents include an ether, anester, an alcohol, a ketone, or a mixture thereof. In certainembodiments, the suitable solvent is methanol, ethanol, isopropanol, oracetone wherein said solvent is anhydrous or in combination with water,methyl tert-butyl ether (MTBE) or heptane. In other embodiments,suitable solvents include tetrahydrofuran, 1,4-dioxane,dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl ethylketone, N-methyl-2-pyrrolidone, methyl t-butyl ether, t-butanol,n-butanol, and acetonitrile. In another embodiment, the suitable solventis anhydrous ethanol. In some embodiments, the suitable solvent is MTBE.

According to another embodiment, the present invention provides a methodfor preparing a solid form of crystalline magnesium glycinate,comprising the steps of dissolving magnesium glycinate with a suitablesolvent and optionally heating to form a solution thereof and isolatingcrystalline hydrated magnesium glycinate.

As described generally herein, magnesium glycinate and/or its precursorsmay be dissolved in a suitable solvent, optionally with heating. Incertain embodiments, magnesium glycinate or its precursors are dissolvedat about 50 to about 60° C. In other embodiments, magnesium glycinate orits precursors are dissolved at about 50 to about 55° C. In still otherembodiments, magnesium glycinate or its precursors are dissolved at theboiling temperature of the solvent. In other embodiments, magnesiumglycinate or its precursors are dissolved without heating (e.g., atambient temperature, approximately 20-25° C.).

In certain embodiments, magnesium glycinate precipitates from themixture. In another embodiment, magnesium glycinate crystallizes fromthe mixture. In other embodiments, magnesium glycinate crystallizes fromsolution following seeding of the solution (i.e., adding crystals ofmagnesium glycinate to the solution).

Crystalline magnesium glycinate can precipitate out of the reactionmixture, or be generated by removal of part or all of the solventthrough methods such as evaporation, distillation, filtration (e.g.,nanofiltration, ultrafiltration), reverse osmosis, absorption andreaction, by adding an anti-solvent (e.g., water, MTBE and/or heptane),by cooling (e.g., crash cooling) or by different combinations of thesemethods.

As described generally above, crystalline magnesium glycinate isoptionally isolated. It will be appreciated that magnesium glycinate maybe isolated by any suitable physical means known to one of ordinaryskill in the art. In certain embodiments, precipitated solid magnesiumglycinate is separated from the supernatant by filtration. In otherembodiments, precipitated solid magnesium glycinate is separated fromthe supernatant by decanting the supernatant. In some embodiments,crystalline magnesium glycinate is separated by evaporation of a solventor supernatant.

In certain embodiments, precipitated solid magnesium glycinate isseparated from the supernatant by filtration.

In certain embodiments, isolated crystalline magnesium dihydrate isdried in air. In other embodiments isolated crystalline magnesiumdihydrate is dried under reduced pressure, optionally at elevatedtemperature.

In some embodiments of the invention, solid forms of magnesium glycinateare obtained through a production process capable of producing a formwith a specified crystal morphology and that is substantially free ofimpurities such as magnesium hydroxide. In some embodiments, theproduction process results in magnesium glycinate dihydrate that issubstantially free of solid impurities. The term “substantially free ofsolid impurities”, as used herein, indicates that the amount of solidimpurities is less than 10%, less than 9%, less than 8%, less than 7%,less than 6%, less than 5%, less than 4%, less than 3%, less than 2% orless than 1% by weight. In a particular embodiment, magnesium glycinatein the form of a dihydrated polymorph is obtained by adding anappropriate amount of glycine to a solution of magnesium methoxide andmethanol, heating the solution, adding an appropriate volume of water tothe solution and cooling the solution to crystallize out magnesiumglycinate dihydrate. The reaction scheme is diagrammed below.

In some embodiments, the magnesium glycinate dihydrate is thepolymorphic form described by the XRPD data above and in FIGS. 1-3.

In some embodiments, a process for the preparation of crystallinemagnesium glycinate dihydrate substantially free of impurities comprisesabout 20 kg±4 kg of magnesium methoxide (6-10% in methanol solution). Insome embodiments, a process for the preparation of crystalline magnesiumglycinate dihydrate substantially free of impurities comprises about 250kg±50 kg of methanol (from 8% solution). In some embodiments, a processfor the preparation of crystalline magnesium glycinate dihydratesubstantially free of impurities comprises about 35 kg±7 kg of glycine.In some embodiments, a process for the preparation of crystallinemagnesium glycinate dihydrate substantially free of impurities comprisesabout 140 kg±28 kg of deionized water.

In some embodiments, a process for the preparation of crystallinemagnesium glycinate dihydrate substantially free of impurities comprisesa water/magnesium methoxide (6-10% in methanol solution) ratio (v/v) ofabout 8:1, about 7:1, about 6.5:1 or about 6:1, or a range between anytwo of the numbers. In some embodiments, a process for the preparationof crystalline magnesium glycinate dihydrate substantially free ofimpurities comprises a water/magnesium methoxide (6-10% in methanolsolution) ratio (v/v) of about 8:1-5:1. In some embodiments, a processfor the preparation of crystalline magnesium glycinate dihydratesubstantially free of impurities comprises a water/glycine weight ratioof about 5:1-3:1. In some embodiments, a process for the preparation ofcrystalline magnesium glycinate dihydrate substantially free ofimpurities comprises a methanol (8% solution)/water ratio (v/v) of about3:1-1:1. In some embodiments, a process for the preparation ofcrystalline magnesium glycinate dihydrate substantially free ofimpurities comprises a methanol (8% solution)/magnesium methoxide ratio(v/w) of about 20:1-10:1.

In particular embodiments of the process, as exemplified in FIG. 4,magnesium methoxide is dissolved in an alcohol such that the magnesiummethoxide is present in an amount of 6-10% in methanol solution. Glycineis then added to the magnesium methoxide solution. In some embodiments,the amount (weight) of glycine added in kilograms is about 1/10^(th) ofthe volume (L) of the solution. In other embodiments, the amount ofglycine added in kilograms is about 1/9^(th), ⅛^(th), 1/7^(th) or moreof the volume (L) of the solution. The mixture of magnesium methoxidesolution and glycine is then heated to about 50-55° C. for approximately30 minutes or more. After heating, water is added to quench thereaction, and the mixture is heated again to 50-55° C. for approximately30 minutes or more. The mixture is cooled or allowed to cool toapproximately 25° C. or less for at least 30 minutes, allowingcrystalline magnesium glycinate dihydrate to precipitate from thesolution. Magnesium glycinate dihydrate is then filtered from thesolution, rinsed with methanol and vacuum dried at a temperature ofapproximately 50-60° C., thereby producing crystalline magnesiumglycinate dihydrate of the forms described herein. Suitable alcoholsinclude those having from 1 to about 12 carbon atoms, including, forexample, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butylalcohol and the like and mixtures thereof. Preferred solvents includemethanol and ethanol, and most preferably methanol.

Those of skill in the art will appreciate that the amount of water inthe reaction mixture determines the type of hydrate that is formed. Theamount of water may be adjusted to form a monohydrate, dihydrate,trihydrate etc.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising the crystalline polymorphs of magnesium dihydrate describedherein and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of crystalline magnesium glycinate (e.g., magnesium glycinatedihydrate) in compositions of this invention may be such that it iseffective to treat hyperphosphatemia in a subject. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient. In certain embodiments of the invention,the formulation for oral administration comprises an enteric coating. Insome embodiments, the enteric coating contains acetyltributyl citrate,carbomers, cellulose acetate phthalate, cellulose acetate succinate,ethyl cellulose, guar gum, hypromellose acetate succinate, hypromellosephthalate, polymethacrylates, polyvinyl acetate phthalate, shellac,tributyl citrate, triethyl citrate, white wax and/or zein.

As described in the '012 application, it has been discovered thatmagnesium salts such as magnesium glycinate may interact differentlywith stomach acid which contains an overwhelming amount of HCl.Magnesium glycinate may react with stomach acid (HCl) to form magnesiumchloride, which does not have the ability to bind phosphate inappreciable quantities. Thus, magnesium glycinate may lose its abilityto precipitate phosphate in SIF and treat hyperphosphatemia. Therefore,it is desirable to enteric coat magnesium salts, in particular magnesiumglycinate, such that magnesium salts are protected from stomach acids.

The term “subject”, as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, Vitamin E polyethylene glycol succinate(d-alpha tocopheryl polyethylene glycol 1000 succinate), sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, and wool fat.

Compositions of the invention can be formulated for administration byinjection, topically, orally, transdermally, or rectally. In someembodiments, a composition of the present invention is formulated fororal administration. Sterile injectable forms of the compositions ofthis invention may be an aqueous or oleaginous suspension. Thesesuspensions may be formulated according to techniques known in the artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous and non-aqueous suspensions orsolutions. In the case of tablets for oral use, carriers commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient istypically combined with emulsifying and suspending agents. If desired,certain sweetening, flavouring, coloring or nutritional agents (e.g.,vitamins, minerals, fatty acids or amino acids) may also be added.

Capsule dosages may contain magnesium glycinate dihydrate substantiallyin the form of a polymorph described herein within a capsule, which maybe coated with gelatin. As mentioned, tablet and powder forms maycomprise an enteric coating. Enteric coatings may comprise phthalic acidcellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinylalcohol phthalate, carboxy methyl ethyl cellulose, a copolymer ofstyrene and maleic acid, a copolymer of methacrylic acid and methylmethacrylate, and like materials, and if desired, they may be employedwith suitable plasticizers and/or extending agents. A coated capsule mayhave a coating on the surface of the capsule or may be a capsulecomprising a powder or granules with an enteric-coating.

As used herein, the term “enteric coating” or “enteric film” refers to abarrier applied to, for example, oral medication that controls thelocation in the digestive system where the medication is absorbed.Typically, enteric coatings prevent release of medication before itreaches the small intestine. In some embodiments, enteric coatingssuitable for the present invention include surface coatings that arestable at the highly acidic pH (e.g., pH ˜3) found in the stomach, butdissolve quickly at a less acidic (relatively more basic) pH (e.g.,(above pH 5.5). According to the present invention, an enteric film orcoating prevents dispersion of magnesium glycinate polymorphs in theacidic environment of the lumen of the stomach.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, joints, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of Compound 1 include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, provided pharmaceutically acceptable compositionscan be formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In some embodiments of the invention, a polymorph of magnesium glycinatedihydrate as described herein is a component of a pharmaceuticalcomposition that also comprises one or more additional therapeuticagents. In certain embodiments, the additional therapeutic agents areintended for the treatment of hyperphosphatemia. In particularembodiments, the additional therapeutic agents are selected from a groupconsisting of aluminium-containing phosphate binders, calcium-containingphosphate binders (e.g., calcium acetate), magnesium salts,phosphate-binding polymers (e.g. sevelamer hydrochloride (Bleyer, A. J.et al., Am. J. Kidney Dis., 1999, 33:694-701)), and lanthanum carbonate(see, e.g., Joy, M. S. et al., Am. J. Kidney Dis., 2003, 42:96-107).Additional magnesium salts that may be included in pharmaceuticalcompositions of the invention include magnesium arginate, magnesiumbetainate, magnesium hydroxide, magnesium lysinate and magnesium oxide.

In some embodiments, a composition of the invention can be a food, adrink, or a nutritional, food or dietary supplement. In one embodiment,the composition is a nutritional supplement. As used herein, “anutritional supplement” is a preparation formulated to supply nutrients(including, but not limited to, vitamins, minerals, fatty acids or aminoacids) that are missing or not consumed in sufficient quantity in aperson's or animal's diet. As used in this application, a nutritionalsupplement is also referred to as “a food supplement” or “a dietarysupplement.”

Uses of Compounds and Pharmaceutically Acceptable Compositions

Phosphate-binding magnesium glycinate forms described herein can be usedto bind and/or remove phosphate from a mammalian subject. In particular,phosphate-binding magnesium polymorphs described herein can be used totreat hyperphosphatemia. As used herein, the term “hyperphosphatemia”refers to a higher than normal blood level of phosphorous. In humanadults, the normal range for blood phosphorous is approximately 2.5-4.5mg/dL (i.e., 2.5-4.5 mg/100 mL). Typically, an individual withhyperphosphatemia condition has fasting serum phosphorus concentrationhigher than 5.0 mg/dL (e.g., higher than 5.5 mg/dL, 6.0 mg/dL, 6.5mg/dL, or 7.0 mg/dL). Methods for measuring phosphate concentrations arewell known in the art. For example, phosphate concentrations can bemeasured by the method of Lowry and Lopez, J. Biol. Chem. 162: 421-428.The hyperphosphatemia condition, especially if present over extendedperiods of time, leads to severe abnormalities in calcium and phosphorusmetabolism and can be manifested by aberrant calcification in joints,lungs, and eyes.

Hyperphosphatemia is associated with various diseases or medicalconditions including, but not limited to, diseases associated withinadequate renal function such as, for example, chronic kidney diseaseand/or end-stage renal disease, hypoparathyroidism, and other disordersof phosphate metabolism and/or impaired phosphate transport function.

In embodiments of the invention, a method of treating hyperphosphatemiaincludes administering to a subject in need of treatment atherapeutically effective amount of a crystalline form of magnesiumglycinate. In some embodiments, the form is a dihydrated polymorph ofmagnesium glycinate, such as the one described in Tables 1-6. In someembodiments, a method of treating hyperphosphatemia includesadministering to a subject in need of treatment a therapeuticallyeffective amount of at least one magnesium glycinate dihydratepolymorph. As used herein, the term “therapeutically effective amount”refers to an amount effective to reduce or control serum phosphate levelor to treat, prevent, and/or delay the onset of the symptom(s) caused byhyperphosphatemia when administered in a single dose or in a series ofdoses separated by appropriate time intervals, such as hours or days, toa subject suffering from or susceptible to a disease, disorder, and/orcondition associated with hyperphosphatemia. A therapeutically effectiveamount is commonly administered in a dosing regimen that may comprisemultiple unit doses. An appropriate unit dose within an effective dosingregimen is referred to as “therapeutically effective dose.”

As used herein, an “individual,” “patient” or “subject” being treatedincludes a human or a non-human such as, a non-human mammalian subjectincluding, but not limited to, a bovine, cat, dog, ferret, gerbil, goat,guinea pig, hamster, horse, mouse, nonhuman primate, pig, rabbit, rat,or sheep. As used herein, a “subject susceptible to” a disease, disorderand/or condition associated with hyperphosphatemia refers to anindividual at risk of developing hyperphosphatemia or to a patientreporting one or more of the physiological symptoms ofhyperphosphatemia, even though a diagnosis of hyperphosphatemia may nothave been made.

As used herein, the term “reduce,” “decrease,” or grammaticalequivalents, indicate values that are relative to a baselinemeasurement, such as a measurement in the same individual prior toinitiation of the treatment described herein, or a measurement in acontrol individual (or multiple control individuals) in the absence ofthe treatment described herein. A “control individual” is an individualafflicted with the same condition of hyperphosphatemia as the individualbeing treated.

As used herein, the term “treat,” “treatment,” or “treating” refers toany method used to partially or completely alleviate, ameliorate,relieve, inhibit, prevent, delay onset of, reduce severity of and/orreduce incidence of one or more symptoms or features ofhyperphosphatemia or of a particular disease, disorder, and/or conditionunderlying hyperphosphatemia. Treatment may be administered to a subjectwho does not exhibit signs of a disease and/or exhibits only early signsof the disease for the purpose of decreasing the risk of developingpathology associated with the disease. For prophylactic benefit, acomposition of the invention may be administered to a patient at risk ofdeveloping hyperphosphatemia or to a patient reporting one or more ofthe physiological symptoms of hyperphosphatemia, even though a diagnosisof hyperphosphatemia may not have been made.

The actual amount effective for a particular application will depend onthe condition being treated (e.g., the disease or disorder and itsseverity, and the age and weight of the patient to be treated) and theroute of administration. Determination of an effective amount is wellwithin the capabilities of those skilled in the art, especially in lightof the disclosure herein. For example, the effective amount for use inhumans can be determined from animal models. For example, a dose forhumans can be formulated to achieve circulating and/or gastrointestinalconcentrations that have been found to be effective in animals.

As described above, solid forms of crystalline magnesium glycinateencompassed by the present invention may be administered using anyamount and any route of administration effective for treating orlessening the severity of hyperphosphatemia. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Crystallinemagnesium glycinate polymorphs (e.g., magnesium glycinate dihydrate) ispreferably formulated in substantially morphological pure dosage unitform for ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

In some embodiments of invention, the unit dosage forms aresubstantially morphologically pure, meaning that they are comprisedsubstantially of only one crystal polymorph. For example, a unit dosagemay be comprised of at least 75%, at least 80%, at least 85%, at least90%, at least 95%, at least 98%, at least 99% or more a single polymorphdescribed herein. In some embodiments of the invention, a unit dose maycomprise at least 98% of the polymorphic form of magnesium glycinatedihydrate described in FIGS. 1-3 and Tables 1-6.

Successful treatment of hyperphosphatemia may be achieved byadministration of the pharmaceutical compositions described above. Insome embodiments, a therapeutically effective dose of a magnesiumglycinate polymorph according to the invention may contain about 20 mgto 1200 mg of magnesium (e.g., about 20 mg to about 1000 mg ofmagnesium, about 20 mg to about 800 mg of magnesium, about 20 mg toabout 600 mg of magnesium, about 20 mg to about 400 mg of magnesium,about 20 mg to about 200 mg of magnesium, about 100 mg to about 300 mgof magnesium, about 100 mg to about 500 mg of magnesium, about 100 mg toabout 700 mg of magnesium, about 100 mg to about 900 mg of magnesium).In some embodiments, a therapeutically effective dose of a magnesiumglycinate polymorph contains less than about 1200 mg of magnesium (e.g.,less than about 1000 mg of magnesium, less than about 800 mg magnesium,less than about 600 mg of magnesium, less than about 400 mg ofmagnesium, or less than about 200 mg magnesium).

In some embodiments, compositions according to the invention, whenadministered according to a suitable dosing regimen, provide atherapeutically effective amount of magnesium glycinate polymorphranging from about 60 mg to about 4000 mg (e.g., from about 80 mg toabout 3000, from about 1000 mg to about 2000 mg, from about 500 mg toabout 1200 mg, from about 500 mg to about 1100 mg, from about 500 mg toabout 1000 mg) per day. In some embodiments, compositions according tothe invention, when administered according to a suitable dosing regimen,provide more than about 500 mg (e.g., more than about 750 mg, more thanabout 1000 mg, more than about 1250 mg, more than about 1500 mg, morethan about 1750 mg, or more than about 2000 mg) magnesium glycinatepolymorph per day. In some embodiments, compositions according to theinvention, when administered according to a suitable dosing regimen,provide less than about 4000 mg (e.g., less than about 3500 mg, lessthan about 3000 mg, less than about 2500 mg, less than about 2000 mg,less than about 1500 mg, or less than about 1000 mg) magnesium glycinatepolymorph per day.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated.

The polymorphs described herein may be administered in combination withone or more additional therapeutic agents such as those described above.The additional agents may be administered separately from a magnesiumglycinate-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a magnesium glycinate polymorph in a single composition.If administered as part of a multiple dosage regime, the two activeagents may be submitted simultaneously, sequentially or within a periodof time from one another (e.g., one hour, two hours, six hours, twelvehours, one day, one week, two weeks, one month).

As used herein, the terms “combination,” “combined,” and related termsrefer to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a magnesiumglycinate polymorph may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a magnesium glycinatepolymorph (e.g., the magnesium glycinate dihydrate as described in FIGS.1-3 and Table 1-6), an additional therapeutic agent, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1 Preparation of Crystalline Magnesium Glycinate Dihydrate

A polymorph of magnesium glycinate dihydrate was prepared by the processdescribed in FIG. 4. Magnesium methoxide (6-10% in methanol solution),methanol, glycine and nitrogen gas were obtained. Raw materialcalculations were conducted as follows:

TABLE 7 Magnesium Glycinate Dihydrate Synthesis Stoichiometry and BatchFactor Calculation Weight Volume Molar Batch Material MW Density KgLiters Moles Equiv Volumes factor Magnesium 86.37 22.00 254.71 1.0 1.000methoxide Active Weight (6-10% solution) Methanol (From 32.04 0.792253.0 319.4 14.5 8% Solution) Glycine 75.07 1.61 38.243 509.43 2.01.7383 Deionized 18.01 1.00 143.7 143.7 6.5 0.568× Water Methanol weightMethanol Rinse 32.04 0.792 50.43 63.8 2.89 2.2924

Using a vacuum, the target amount of magnesium methoxide (in methanolsolution) was transferred into a primary 200-gallon reactor. The netactive amount of magnesium methoxide in the solution was determined bymultiplying the net solution weight by the solution assay and thendividing the result by 100. The target amount of magnesium methoxide wasthe net active magnesium methoxide weight in the solution. Magnesiummethoxide was the limiting reagent in the reaction.

The target amount of glycine was transferred into clean polyethylene(LDPE) bags. The magnesium methoxide solution in the 200-gallon reactorwas stirred while the glycine was transferred into the reactor whilenitrogen purge of the reactor head space was maintained. After all ofthe glycine had been added, the temperature of the reactor contents washeated to 50-55° C. with a maximum jacket temperature of 70° C. Thereactor was maintained at this temperature for at least 30 minutes.Meanwhile, the net amount of methanol in the magnesium methoxidesolution was determined by subtracting the net active weight of themagnesium methoxide from the total solution weight.

The target weight of deionized water for quenching was calculated bymultiplying the total methanol weight by a factor of 0.568. The targetweight of deionized water was then transferred to the primary reactorover a period of at least 5 minutes. The reactor contents were againheated to 50-55° C. with a maximum jacket temperature of 70° C., andmaintained at said temperature for at least 30 minutes.

After at least 30 minutes, the reactor was cooled to approximately15-25° C. and maintained at said temperature for at least 30 minutes. Atthe end of 30 minutes, abundant precipitate crystals were present in thesolution.

The precipitated crystals were collected by a vacuum filter dryer. Amagnesium glycinate dihydrate slurry was filtered on the filter dryingusing recirculated mother liquor as necessary to facilitate the transferof the slurry. The solid was collected and lightly compressed into afilter cake.

The filter cake was de-liquored for at least 10 minutes by blowingnitrogen through the filter cake. A targeted amount of methanol rinsewas then used to wash the magnesium glycinate. The methanol rinse wastransferred to the filter dryer and the collected magnesium glycinatedihydrate washed by displacement washing. After the wash was complete,the collected magnesium glycinate dihydrate was de-liquored for at least10 minutes by blowing nitrogen through the filter cake.

Wet magnesium glycinate dihydrate filter cake was then transferred to avacuum shelf dryer (Stokes) and dried under at least 28 inches Hg ofpressure at 50-60° C. for at least 12 hours. The weight of the filtercake was monitored during drying. Drying continued until the magnesiumglycinate dihydrate reached a constant weight (less than or equal to 1%loss over 4 hours of drying).

Example 2 X-ray Diffraction Experiments Single Crystal X-Ray Analysis

A single crystal of the magnesium glycinate dihydrate (identificationcode d12119) was isolated from a powder sample prepared as above. Theisolated crystal was analysed by X-ray crystallography. Data werecollected on a Bruker Kappa APEX-DUO diffractometer using a Copper ImuS(microsource) tube with multi-layer optics and were measured using acombination of φ scans and ω scans. The data was processed using APEX2and SAINT (Bruker, 2007, APEX2, SAINT & SADABS, Bruker AXS Inc.,Madison, Wis., USA). Absorption corrections were carried out usingSADABS (Bruker, 2007). The structure was solved and refined usingSHELXTL (Sheldrick, G. M., Acta. Cryst., 2008, A64: 112-122) forfull-matrix least-squares refinement that was based on F². All H atomsbonded to C atoms were included in calculated positions and allowed torefine in riding-motion approximation with U˜iso˜tied to the carrieratom. H atoms bonded to O and N atoms were refined independently withisotropic displacement parameters.

The following results were obtained:

TABLE 8 Empirical formula C₄H₁₂MgN₂O₆ Formula weight  208.47 Temperature147(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P21/n Unit cell dimensions a = 7.5481(3) Å α = 90° b = 9.0525(3) Å β =98.612(3)° c = 12.9702(5) Å γ = 90° Volume 876.25(6) Å³ Z   4 Density(calculated) 1.580 Mg/m³ Absorption coefficient 1.893 mm⁻¹ F(000)  440Crystal size 0.10 × 0.01 × 0.01 mm³ Theta range for data collection 5.98to 66.64° Index ranges −8 <= h <= 7, −10 <= k <= 10, −10 <= l <= 15Reflections collected 5746 Independent reflections 1501 [R(int) =0.0279] Completeness to theta = 66.64° 97.2% Absorption correctionSemi-empirical from equivalents Max. and min. transmission 0.7528 and0.6842 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 1501/0/150 Goodness-of-fit on F²   1.056Final R indices [I > 2sigma(I)] R1 = 0.0269, wR2 = 0.0696 R indices (alldata) R1 = 0.0303, wR2 = 0.0718 Largest diff. peak and hole 0.215 and−0.224 e · Å⁻³

Crystal structures defined by these parameters are represented in FIGS.2 and 3. These experiments confirmed that the process of Example 1resulted in a single dihydrated polymorph of magnesium glycinate.

X-Ray Powder Diffraction Analysis

Two samples of magnesium glycinate dihydrate powder prepared as abovewere submitted for X-ray Powder Diffraction Analysis (“XRPD”). Theanalysed lot numbers were designated as 428-192 and 428-194. Powdersamples were gently packed in standard sample holders. Excess powder wasremoved by a glass edge to achieve a flat surface and minimize theorientation of the crystallites in the packed powder.

Both samples were run on an automated Siemens/Brukker D5000diffractometer. The system was equipped with a high power line focusCu-kα source operating at 50 kV/35 mA. A solid-state Si/Li Kevexdetector was used for removal of k-beta lines. The diffractometer andthe detector were periodically calibrated with provided Quartz ceramicplate for zero-correction.

The diffraction patterns were collected on a theta/2-thetaBragg-Brentano reflection geometry with fixed slits as follow:divergence slit 1.0 mm, scattering slit 1.0 mm and receiving slit of 0.2mm. A step scan mode was used for data acquisition with step size of0.02° 2-theta and counting time of 1.5 s. per step. Data processing wascarried out with Bruker AXS software Eva™ v.8.0.

XRPD analysis (FIG. 1) showed the material to be crystalline and capableof being unambiguously characterized by at least one characteristic peakidentified by 2-theta values as follows:

TABLE 9 No. 2-Theta ° Δ 2θ (±)° d, Å 1 14.6 0.1 6.06 2 16.0 0.1 5.54 316.9 0.1 5.25 4 17.6 0.1 5.04 5 19.3 0.1 4.59 6 22.9 0.1 3.88 7 24.4 0.13.65 8 25.8 0.1 3.46 9 30.9 0.1 2.89 10 47.1 0.1 1.93

The results of a single crystal X-ray analysis are limited to onecrystal placed in a X-ray beamXRPD provides crystallographic data on alarge group of crystals. If the powder is a pure crystalline compound, asimple powder diagram is obtained. To compare the results of a singlecrystal analysis and powder X-ray analysis, the single crystal data canbe computationally converted into a powder X-ray diagram. An XRPDpattern can be calculated from single crystal X-ray diffraction becausethe single crystal experiment routinely determines the unit celldimensions, space group, and atomic positions. By comparing thiscalculated powder pattern and the powder pattern experimentally obtainedfrom a large collection of crystals, it is possible to confirm if theresults of the two techniques are the same; i.e., if the crystals in theXRPD samples match the structure of the single crystal.

This experiments was conducted on two powders samples (designatedDL-428-194 and DL-428-192), which were compared to a calculated XRPDpattern from the single-crystal analysis above. The results are shown inFIG. 1. The upper two plots corresponds to the experimentally derivedXRPD pattern for their respective samples, and the second plotcorresponds to the XRPD calculated from the single crystal X-ray data.

The peak overlap indicated that the two techniques yield the sameresults. The primary powder X-ray diffraction peaks provided anunambiguous description of a polymorph of magnesium glycinate dihydrateproduced by the process of Example 1. Identical patterns from twoseparate samples indicated that the process routinely produces the samepolymorph. The near perfect similarity between the primary X-ray powderdiffraction peaks of the samples and the peaks calculated from thecrystal structure indicated that the process of Example 1 resulted in amorphological pure single polymorph matching the crystal structuredescribed in Tables 2-6. The lattice parameters for the bulk materialdiffered slightly from the ones obtained from the single crystalstructure solution. This is common in the field and was due to the factthat the single crystal experiment was carried out at low temperature(−120° C.), while the x-ray powder diffraction data was collected atroom temperature. At low temperature most of the molecular structurestend to shrink their lattices.

Example 3 Phosphate Binding Assays

Exemplary stock solutions suitable for phosphate-binding assays includethe following: phosphate-binding solution (“PBS”) containing 10 mMKH₂PO₄, 30 mM Na₂CO₃, 80 mM NaCl, as described in Rosenbaum et al.Nephrol. Dial. Transplant. 12:961-964 (1997); acetate buffer (“AB”)solution containing 0.1N acetic acid, 0.025N sodium acetate, asdescribed in Lowry & Lopez J. Biol. Chem. 162:421-428 (1946); ammoniummolybdate (“AM”) solution containing 1% ammonium molybdate in 0.05NH₂SO₄, as described in Lowry & Lopez; ascorbic acid (“AA”) solutioncontaining 1% ascorbic acid in H₂O, as described in Lowry & Lopez.

In general, the phosphate-binding assays are conducted in 12×75 mm glasstubes. 4.0 mL PBS and 20 mg putative phosphate binder are added to aglass tube and then mixed for 1 h at room temperature. 0.1 mLsupernatant is pipetted from this tube to a new test tube. 3.0 mL AB,0.3 mL AA and 0.3 mL AM solutions are added and O.D. is measured at 700nm after 10 minutes. The assay is linear over the range used in thisexample.

The phosphate binding capacity was calculated as follows (mcg stands formicrograms):((O.D. of sample×95)/O.D. of standard)×40=(mcg)PO₄ left in solution((3800(mcg)PO₄ left)×50)/1000=(mcg)PO₄ bound per gram of phosphatebinder.

The phosphate binding capacities of samples of magnesium glycinatedihydrate produced by the process of Example 1 are measured. X-raypowder diffraction is conducted on each of the samples to verify thatthey consist of the polymorph described in Example 2. Hypotheticalresults are presented below:

TABLE 10 Exemplary phosphate-binding results Sample PO₄ binding, mg/g 1175.0 2 177.0 3 176.2 4 178.1

Considering a degree of experimental error inherent in the phosphatebinding assays, each sample of the polymorph possesses a substantiallyequivalent phosphate binding capacity, suggesting that thephosphate-binding capacity of a magnesium glycinate salt is related tothe process by which the salt is produced and the type of crystalsproduced by the process.

Example 4 Preparation of an Oral Formulation with an Enteric Coating

An oral formulation that contains the magnesium glycinate dihydratepolymorph of Example 2 is prepared as follows. The magnesium glycinatedihydrate polymorph of the examples above, one excipient suitable forenteric coating, one or more pharmaceutically acceptable excipients, andother appropriate ingredients (e.g., a lubricant) are mixed until adegree of uniformity suitable for pharmaceutical formulation is reached.The mixture is shaped into tablets or caplets. Tablets or caplets arethen coated with at least one excipient suitable for enteric coating.

Example 5 Treatment of Hyperphosphatemia

An oral formulation containing the magnesium glycinate dihydratepolymorph prepared as described in the examples above is used to treathuman patients suffering from hyperphosphatemia. Therapeuticformulations may be prepared to comprise a unit dose of 300 mg magnesiumglycinate. One patient who has not taken a phosphate-binder may have aserum phosphorus level between about 5.5 and about 7.5 mg/dL. Two unitsof the formulation are orally administered to the patient three timesdaily with meals. A second patient has a serum phosphorus level betweenabout 7.5 and about 9.0 mg/dL and has not taken a phosphate binder.Three units of the same formulation are orally administered to thepatient three times daily with meals. The third patient has a serumphosphorus level greater than about 9.0 mg/dL and has not taken aphosphate binder. Four units of the formulation are orally administeredto the patient three times daily with meals.

In each case, a patient's serum phosphorus level may be reduced to andremain in the range from 3.5 to 5.5 mg/dL after treatment according tothe dosing regimen described above. A dosing regimen can be maintainedrelatively unchanged when the serum phosphorus level is within the rangeof 3.5 to 5.5 mg/dL.

INCORPORATION OF REFERENCES

All publications and patent documents cited in this application areincorporated by reference in their entirety to the same extent as if thecontents of each individual publication or patent document wereincorporated herein.

What is claimed is:
 1. A crystalline dihydrate form of magnesium glycinate (Formula I)

wherein the form is characterized by an X-ray powder diffraction pattern having one or more peaks selected from those at about 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1.
 2. The form of claim 1, wherein the form is characterized by an X-ray powder diffraction pattern having two or more peaks selected from those at about 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1.
 3. The form of claim 1, wherein the form is characterized by an X-ray powder diffraction pattern having three or more peaks selected from those at about 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1.
 4. The form of claim 1, wherein the form has all of the peaks in its X-ray powder diffraction pattern selected from those at about 14.6, 16.0, 16.9, 17.6, 19.3, 22.9, 24.4, 25.8, 30.9 or 47.1.
 5. The form of claim 4, having all of the peaks in its X-ray powder diffraction pattern selected from those at about: No. 2-Theta ° Δ 2θ (±)° d, Å 1 14.6 0.1 6.06 2 16.0 0.1 5.54 3 16.9 0.1 5.25 4 17.6 0.1 5.04 5 19.3 0.1 4.59 6 22.9 0.1 3.88 7 24.4 0.1 3.65 8 25.8 0.1 3.46 9 30.9 0.1 2.89 10 47.1 0.1 1.93.


6. The form of claim 1, wherein the crystalline magnesium glycinate dihydrate has a space group P21/n.
 7. The form of claim 1, wherein the crystalline magnesium glycinate dihydrate has unit cell dimensions of about a=7.5 Å, b =9.0 Å, and c=13.0 Å.
 8. The form of claim 7, wherein the crystalline magnesium glycinate dihydrate has unit cell dimensions of about a=7.548 Å, b=9.053 Å, and c=12.970 Å.
 9. The form of claim 7, wherein the crystalline magnesium glycinate dihydrate has unit cell dimensions of about a=7.575 Å, b =9.153 Å, and c=13.052 Å.
 10. A crystalline magnesium glycinate dihydrate form characterized by one or more of the following crystal structure parameters: Crystal system Monoclinic Space group P 21/n Unit cell dimensions a = 7.5481(3) Å α = 90° b = 9.0525(3) Å β = 98.612(3)° c = 12.9702(5) Å γ = 90° Volume 876.25(6) Å³ Z   4 Density (calculated) 1.580 Mg/m³ Absorption coefficient 1.893 mm⁻¹ F(000)  440 Crystal size 0.10 × 0.01 × 0.01 mm³ Theta range for data collection 5.98 to 66.64° Index ranges −8 <= h <= 7, −10 <= k <= 10, −10 <= l <= 15 Reflections collected 5746 Independent reflections 1501 [R(int) = 0.0279] Completeness to theta = 66.64° 97.2% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7528 and 0.6842 Refinement method Full-matrix least-squares on F² Data/restraints/parameters 1501/0/150 Goodness-of-fit on F²   1.056 Final R indices [I > 2sigma(I)] R1 = 0.0269, wR2 = 0.0696 R indices (all data) R1 = 0.0303, wR2 = 0.0718 Largest diff. peak and hole 0.215 and −0.224 e · Å⁻³.


11. A pharmaceutical composition comprising the crystalline form of magnesium glycinate dihydrate as described in claim
 1. 12. The pharmaceutical composition of claim 11, further comprising an enteric coating.
 13. The pharmaceutical composition of claim 12, wherein the enteric coating comprises acetyltributyl citrate, carbomers, cellulose acetate phthalate, cellulose acetate succinate, ethyl cellulose, guar gum, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate, shellac, tributyl citrate, triethyl citrate, white wax and/or zein.
 14. The pharmaceutical composition of claim 12, wherein the enteric coating is stable at pH less than 3 but dissolves at a pH above 5.5.
 15. The pharmaceutical composition of claim 12, wherein the composition further comprises one or more additional therapeutic agents or nutrients.
 16. The pharmaceutical composition of claim 15, wherein the nutrient is selected from vitamins, minerals, fatty acids, and/or amino acids.
 17. A method of treating hyperphosphatemia in a subject, the method comprising administering to the subject a form of magnesium glycinate dihydrate according to claim
 1. 